1. Field of the Invention
The present invention is directed to a novel stereocontrolled process for producing a key intermediate used in the synthesis of carbapenem and penem antibiotics.
2. Description of the Prior Art
The present invention is directed to a novel stereocontrolled process for converting 6-aminopenicillanic acid to an optically active azetidinone intermediate of the formula ##STR2## wherein R" is a conventional hydroxy-protecting group and wherein the absolute configuration at carbons 1', 3 and 4 is R, R and R. Intermediates of formula I, which are known per se, are key intermediates in the synthesis of carbapenem and penem antibiotics having an (R)-hydroxyethyl substituent at the 6-position of the carbapenem of penem nucleus and the absolute configuration R and S at the 5 and 6 positions, respectively. A wide variety of such compounds, including the natural fermentation product thienamycin, have been reported in the patent and scientific literature as having exceptional antibacterial activity.
Several total synthesis procedures have been reported for preparation of the above-described penem and carbapenem antibiotics, but to date such procedures have been unsatisfactory from a commercial standpoint due to the large number of steps required and the necessity of separating diastereomer mixtures formed in such procedures.
One approach to synthesis of carbapenems and penems of the above-described type has been to use as a starting material, 6-aminopenicillanic acid (6-APA), a readily-available substance easily obtained by fermentation procedures. Hirai, et al. in Heterocycles 17: 201-207 (1982) report a process for converting 6-APA to the optically active 4-acetoxy-3-azetidinone of the formula ##STR3## which can be converted, by known procedures, to biologically active penems and carbapenems. In this process 6-APA is converted to the above-indicated azetidinone by the following scheme: ##STR4## To elaborate, 6-APA is esterified to give the methyl ester and then converted by known methods, e.g. those described in U.K. 2,045,755A, to give the methyl ester of 6,6-dibromopenicillin. This ester is then hydroxyethylated by the metal-halogen exchange process described in J. Org. Chem. 42: 2960-2965 (1977) to give a mixture of cis and trans diastereomers which, at least on a small scale, can be chromatographically separated to yield the desired (R)-hydroxyethyl cis-isomer. This isomer is silylated with t-butyldimethylchlorosilane to give the corresponding hydroxy-protected intermediate which is then subjected to reductive debromination with Zn to give a mixture of the cis and trans (R)-hydroxyethyl products from which the desired trans isomer can be separated. The hydroxyethylated penicillin ester is then treated with Hg(OAc).sub.2 in acetic acid to cleave the thiazolidine ring and form a 4-acetoxyazetidinone intermediate which is oxidized with KMnO.sub.4 to remove the .beta.-methylcrotonate moiety and form the desired optically active 4-acetoxyazetidinone intermediate.
Tetrahedron Letters 23(39): 4021-4024 (1982) described the following reaction scheme: ##STR5## Thus, the diazopenicillin ester starting material was converted into benzyl 6,6-bis(phenylselenyl)penicillinate which was hydroxyethylated with MeMgBr and CH.sub.3 CHO at -60.degree. C. to give a mixture of diastereomers from which the desired cis isomer can be isolated.
The optically active 4-acetoxyazetidinone can be used in known procedures in the synthesis of carbapenem and penem antibiotics. For example, Tetrahedron Letters 23(22): 2293-2296 (1982) describes conversion of this intermediate to thienamycin and Chem. Pharm. Bull. 29(11): 3158-3172 (1981) describes use of this intermediate to prepare penem antibiotics.
While the above-described procedures are potentially useful for large scale synthesis of (8R)-hydroxyethyl penem and carbapenem antibiotics, they suffer from a lack of stereospecificity in the aldol condensation step and in the reduction step, i.e. hydroxyethylation of the dibromopenicillin or bis(phenylselenyl)penicillin ester and reduction of such hydroxyethylated intermediates to remove the bromo or phenylseleno group gives a mixture of diastereomers which must be separated to give the desired optically active product. Such a separation, particularly on a commercial scale, results in the procedures being much less efficient than they might otherwise be.